Protein polymer hydrogels by in situ, rapid and reversible self-gelation (original) (raw)
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Journal of The American Chemical Society, 2010
Multidomain Peptides are a class of amphiphilic self-assembling peptides with a modular ABA block motif in which the amphiphilic B block drives self-assembly while the flanking A blocks, which are electrostaticly charged, control the conditions under which assembly takes place. Previously we have shown that careful selection of the amino acids in the A and B blocks allow one to control the self-assembled fiber length and viscoelastic properties of formed hydrogels. Here we demonstrate how the modular nature of this peptide assembler can be designed for biological applications. With control over fiber length and diameter, gelation conditions and viscoelastic properties, we can develop suitable materials for biological applications. Going beyond a simple carrier for cell delivery, a biofunctional scaffold will interact with the cells it carries promoting advantageous cell-matrix interactions. We demonstrate the design of a multidomain peptide into a bioactive variant by incorporation of a matrix metalloprotease-2 (MMP-2) specific cleavage site and cell adhesion motif. Gel formation and rheological properties were assessed and compared to related peptide hydrogels. Proteolytic degradation by collagenase IV was observed in a gel weight loss study, and confirmed by specific MMP-2 degradation monitored by mass spectrometry and cryo-TEM. Combination of this cleavage site with the cell adhesion motif RGD resulted in increased cell viability, cell spreading, and encouraged cell migration into the hydrogel matrix. Collectively the structural, mechanical and bioactive properties of this multidomain peptide hydrogel make it suitable as an injectable material for a variety of tissue engineering applications.
Pharmaceutics, 2018
Hydrogels evolved as an outstanding carrier material for local and controlled drug delivery that tend to overcome the shortcomings of old conventional dosage forms for small drugs (NSAIDS) and large peptides and proteins. The aqueous swellable and crosslinked polymeric network structure of hydrogels is composed of various natural, synthetic and semisynthetic biodegradable polymers. Hydrogels have remarkable properties of functionality, reversibility, sterilizability, and biocompatibility. All these dynamic properties of hydrogels have increased the interest in their use as a carrier for peptides and proteins to be released slowly in a sustained manner. Peptide and proteins are remarkable therapeutic agents in today's world that allow the treatment of severe, chronic and life-threatening diseases, such as diabetes, rheumatoid arthritis, hepatitis. Despite few limitations, hydrogels provide fine tuning of proteins and peptides delivery with enormous impact in clinical medicine. Novels drug delivery systems composed of smart peptides and molecules have the ability to drive self-assembly and form hydrogels at physiological pH. These hydrogels are significantly important for biological and medical fields. The primary objective of this article is to review current issues concerned with the therapeutic peptides and proteins and impact of remarkable properties of hydrogels on these therapeutic agents. Different routes for pharmaceutical peptides and proteins and superiority over other drugs candidates are presented. Recent advances based on various approaches like self-assembly of peptides and small molecules to form novel hydrogels are also discussed. The article will also review the literature concerning the classification of hydrogels on a different basis, polymers used, "release mechanisms" their physical and chemical characteristics and diverse applications.
Synthesis of Enzyme-Degradable, Peptide-Cross-Linked Dextran Hydrogels
Bioconjugate Chemistry, 2007
Hydrogels derived from synthetic polymers have been previously engineered to degrade under the activity of matrix metalloproteinases (MMPs). It is believed that these systems can act as extracellular-matrix (ECM) equivalents mimicking the degradation and remodeling of the ECM through the activity of cell-secreted enzymes. In this study, MMP-sensitive hydrogels derived from dextran were developed. In order to avoid the incorporation of hydrolyzable esters often introduced in dextran modification strategies, the polysaccharide was modified with p-maleimidophenyl isocyanate (PMPI) thereby introducing maleimide functionalities in the backbone and resulting in dextran derivatized with p-maleimidophenyl isocyanate (Dex-PMPI). This strategy was favored to separate out the effects of random hydrolysis and enzymatic digestion in the degradation of the dextran hydrogels. A peptide cross-linker, derived from collagen and susceptible to gelatinase A (MMP-2) digestion, was synthesized with bifunctional cysteine termini and used to cross-link the Dex-PMPI. These hydrogels were found to be hydrolytically stable for more than 200 days yet degraded either within 30 h when exposed to bacterial collagenase or within 16 days when exposed to human MMP-2, demonstrating enzymatic-mediated digestion of the peptide crosslinks. Further modification of the cross-linked hydrogels with laminin-derived peptides enhanced cell adhesion and survival, demonstrating the potential of these materials for use in tissue engineering applications.
The in vivo performance of an enzyme-assisted self-assembled peptide/protein hydrogel
Biomaterials, 2011
We demonstrate the distribution of the important extracellular matrix protein laminin in a novel biomaterial consisting of a hydrogel underpinned by nanofibrillar networks. These are formed by the immobilised enzyme mediated self-assembly of fmoc-L 3 (9-fluorenylmethoxycarbonyl-tri-leucine). The peptide assembly yields nanofibrils formed of b-sheets that are locked together via p-stacking interactions. This ordering allows the localisation of the peptide sidechains on the surface, creating a hydrophobic environment. This induces the formation of bundles of these nanofibrils producing a clear hydrogel. This mechanism enables the three dimensional distribution of laminin throughout the network via supramolecular interactions. These forces favour the formation and improve the order of the network itself, as observed by spectroscopic and mechanical testing. In order to test the stability and suitability of this class of material for in vivo applications, we utilise microinjection to deliver the biomaterial under fine spatial control into a dystrophic zebrafish model organism, which lacks laminin as a result of a genetic mutation. Using confocal and transmission electron microscopy, we confirm that the biomaterial remains stable structurally, and is confined spatially to the site of injection.
Understanding the multifaceted nature of peptide hydrogels in biomedical research
Academia Materials Science, 2024
Hydrogels are networks of three-dimensional cross-linked polymers which possess the capacity to absorb and retain water. Hydrogels have proven to be adaptable and versatile, making them useful in various biomedical applications such as tissue engineering and regenerative medicine. Among the various types of hydrogels, Peptide-based hydrogels are most suited for biological applications due to their special features which include biodegradability, mechanical stability, biocompatibility, capacity to retain more water, injectability, and elasticity like that of tissues. In this review, we will present the recent advancements that have occurred in the field of peptide-based hydrogels concerning its biomedical applications especially delivery of Targeted delivery, Wound healing, Tissue engineering, Stem cell Therapy, etc.
Cellulose, 2019
Biomedical/pharmaceutical applications demand hydrogels made from biobased materials without the use of potentially toxic or denaturizing crosslinking agents. In this work, a new all-polysac-charide self-assembling hydrogel system consisting of anionic TEMPO-oxidized cellulose nanofibers (TOCNs) and cationic guar gum (CGG) is proposed. The TOCNs/CGG hydrogel are formed in situ when TOCNs and CGG are mixed, due to the electrostatic interactions and abundant hydrogen bondings therein. Interactions in the hydrogel were supported by Fourier transform infrared spectroscopy (FTIR) results. The as-prepared hydrogel showed good injectability, self-healing performance and reasonable mechanical properties. Scanning electron microscope (SEM) images illustrated the network structure of the hydrogel. Furthermore, the TOCNs/CGG hydrogel system was studied for protein drug release, in which bovine serum albumin (BSA) was used as a model drug to examine the drug release performance in buffers at pH 2.0 or 7.4, simulating gastrointestinal tract conditions. The results indicate its sustained drug releasing ability. A mathematical analysis of the release results supports
Anticancer Supramolecular Hydrogel of D/L-Peptide with Enhanced Stability and Bioactivity
Journal of biomedical nanotechnology, 2018
Supramolecular nanofibers based on D-amino acid-containing peptide self-assembly have attracted increased interest recently because of their superior biostability. However, the construction of nanostructures containing D-amino acids is still insufficient at present, and their application in biomedical fields should be further explored. Herein, we demonstrated that the aggregation property of hydrophobic anticancer tyroservaltide (YSV) could be decreased by introducing D-amino acids. Using such strategy, we fabricated a novel anticancer hydrogelator based on the D/L-peptide of NapGDFDFDYGYSV (D-YSV). Through a heating-cooling process, NapGDFDFDYGYSV self-assembled into a stable hydrogel, while its control peptide of NapGFFYGYSV (L-YSV) self-assembled into an unstable suspension. The nanofiber of D-YSV exhibited an excellent resistance to proteinase digestion comparing with that of L-YSV, and a better anticancer efficiency in vitro due to its improved cellular uptake. Moreover, D-YSV ...
Journal of controlled release : official journal of the Controlled Release Society, 2015
Thermosensitive injectable hydrogels have been used for the delivery of pharmacological and cellular therapies in a variety of soft tissue applications. A promising class of synthetic, injectable hydrogels based upon oligo(ethylene glycol) methacrylate (OEGMA) monomers has been previously reported, but these polymers lack reactive groups for covalent attachment of therapeutic molecules. In this work, thermosensitive, amine-reactive and amine-functionalized polymers were developed by incorporation of methacrylic acid N-hydroxysuccinimide ester or 2-aminoethyl methacrylate into OEGMA-based polymers. A model therapeutic peptide, bivalirudin, was conjugated to the amine-reactive hydrogel to investigate effects on the polymer thermosensitivity and gelation properties. The ability to tune the thermosensitivity of the polymer in order to compensate for peptide hydrophilicity and maintain gelation capability below physiological temperature was demonstrated. Cell encapsulation studies using ...
Biomacromolecules, 2005
Toward the development of synthetic bioactive materials to support tissue repair, we present here the design, production, and characterization of genetically engineered protein polymers carrying specific key features of the natural extracellular matrix, as well as cross-linking with functionalized poly(ethylene glycol) (PEG) to form hybrid hydrogel networks. The repeating units of target recombinant protein polymers contain a cell-binding site for ligation of cell-surface integrin receptors and substrates for plasmin and matrix metalloproteinases (MMPs), proteases implicated in wound healing and tissue regeneration. Hydrogels were formed under physiological conditions via Michael-type conjugate addition of vinyl sulfone groups of endfunctionalized PEG with thiols of cysteine residues, representing designed chemical cross-linking sites within recombinant proteins. Cross-linking kinetics was shown to increase with the pH of precursor solutions. The elastic moduli (G′) and swelling ratios (Q m) of the resulting hydrogels could be varied as a function of the stoichiometry of the reacting groups and precursor concentration. Optima of G′ and Q m , maximum and minimum, respectively, were obtained at stoichiometry ratios r slightly in excess of 1 (r) cysteine/vinyl sulfone). The pool of technologies utilized here represents a promising approach for the development of artificial matrixes tailored for specific medical applications.